The present invention relates to novel diamide compounds and medicines useful in preventing and treating allergic immunological diseases, comprising such a compound as an active ingredient.
IgE, which is a kind of immunoglobulin (Ig), is an allergen-specific molecule produced by an IgE producing cell differentiated from a B cell. This process is triggered by the contact of an immunocyte with an allergen in vivo.
IgE is produced in a target organ for an allergy and binds to a receptor on the surface of a mast cell, which is a central effector cell in an allergic reaction (sensitized state), or basophil. After the sensitization, allergic chemical mediators such as histamine, leukotrienes, prostaglandins and PAF, and injuring enzymes such as triptase are released from the mast cell stimulated by the reaction of the specific IgE and the allergen which invades in the living body, so that immediate responses, such as vascular permeability acceleration, smooth muscle constriction, and vasodilation are elicited. Further, cytokines such as IL-4, which directly activate other immune system cells, are also secreted from the stimulated mast cell. As a result, eosinophils, basophils and the like infiltrate into a tissue, and the allergic chemical mediators and tissue injuring proteins such as MBP, which are secreted by these inflammatory cells, induce a late response, so that the allergic symptom is lingered and taken seriously ill.
From this, IgE is considered a substance fundamentally participating in the attack of an allergic immunological disease.
Therefore, several compounds having an inhibitory effect on the production of an IgE antibody have been found and reported to date with a view toward developing antiallergic agents [Pharmacology and Therapy, 1994, 22(3), 1369; Japanese Patent Application Laid-Open No. 106818/1989; Japanese Patent Publication No. 17506/1995; and Japanese Patent Application Laid-Open No. 92216/1996]. However, the object has been not always sufficiently achieved under the circumstances.
Accordingly, it is an object of the present invention to find a compound having a strong inhibitory effect on the production of an IgE antibody so as to provide a medicine effective for allergic immunological diseases, comprising this compound as an active ingredient.
With the foregoing circumstances in view, the present inventors have carried out an extensive investigation. As a result, it has been found that novel diamide compounds represented by the general formula (1), which will be described subsequently, salts thereof, or hydrates or solvates thereof have an excellent inhibitory effect on the production of an IgE antibody and are useful for medicines such as antiallergic agents, thus leading to completion of the present invention.
According to the present invention, there is thus provided a compound represented by the following general formula (1): 
wherein
A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, isoindolyl, quinolyl or isoquinolyl group which may be substituted;
B is a group of xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(CHxe2x95x90CH)2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94CHxe2x95x90CHxe2x80x94, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine; and
W is a formula 
or 
in which X is 
or 
Y1, Y2 and Y3 are the same or different from one another and are independently a hydrogen atom, xe2x80x94COOR1 (R1 is a hydrogen atom or a lower alkyl group), xe2x80x94CON(R2)R3 (R2 and R3 are the same or different from each other and are independently a hydrogen atom, or a hydroxyl or lower alkyl group), xe2x80x94CH2xe2x80x94N(R4)R5 (R4 and R5 are the same or different from each other and are independently a hydrogen atom or a lower alkyl group, or R4 and R5 may form, together with the adjacent nitrogen atom, a heterocyclic ring which may further have an oxygen, nitrogen or sulfur atom), or xe2x80x94CH2xe2x80x94Sxe2x80x94R6 (R6 is a lower alkyl, phenyl or pyridyl group), or Y1 and Y2 may couple to each other to form an alkylene group which may be through an oxygen, a nitrogen or a sulfur, Z is a benzene or pyridine ring, and n is an integer of 2 or 3, with the proviso that when B is a p-phenylene group, and W is a 1,4-piperazinyl group, A is not a phenyl group, and when B is xe2x80x94CHxe2x95x90CHxe2x80x94, A is not a phenyl group which may be substituted,
or a salt thereof, or a hydrate or solvate thereof.
According to the present invention, there is also provided a medicine comprising the above compound as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above compound and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided use of the above compound for a medicine.
According to the present invention, there is yet still further provided a method of treating an allergic immunological disease, which comprises administering an effective amount of the above compound.
The amide compounds according to the present invention are represented by the general formula (1). In these compounds, the lower alkyl groups include linear or branched alkyl groups having 1-8 carbon atoms. Specific examples thereof include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl and octyl groups. Of these, those having 1-6 carbon atoms, for example, methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl and n-hexyl groups, are particularly preferred.
The lower alkoxy groups include linear or branched alkoxy groups having 1-8 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy and octyloxy groups. Of these alkoxy groups, those having 1-6 carbon atoms are preferred.
The halogen atoms include fluorine, chlorine, bromine and iodine atoms.
In the formula (1), A is a phenyl, naphthyl, dihydronaphthyl, indenyl, pyridyl, indolyl, i-indolyl, quinolyl or i-quinolyl group. These groups may have 1-3 substituents. Here, examples of the substituents on these groups include a hydroxyl group, halogen atoms, lower alkyl groups which may be substituted by 1-3 halogen atoms, lower alkoxy groups, an amino group which may be substituted by one or two lower alkyl groups, and alkylthio groups.
Particularly preferable examples of A include tri-lower alkoxy-phenyl groups.
In B, examples of the substituent on the divalent residue of benzene, pyridine, pyrimidine or pyrazine include nitro, amino, lower alkyl and lower alkoxy groups, and halogen atoms.
More preferred as B is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94(CHxe2x95x90CH)2xe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Cxe2x89xa1Cxe2x80x94, or a divalent residue of benzene, pyridine, pyrimidine or pyrazine. Of these, xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94Cxe2x89xa1Cxe2x80x94 and a benzene residue (phenylene group) are particularly preferred.
In the general formula (1), preferable example of the heterocyclic ring which is formed by R4 and R5 together with the adjacent nitrogen atom include those having 3-10 carbon atoms. Specific examples thereof include pyrrolidine, oxazole, isoxazole, thiazole, isothiazole, imidazole, imidazoline, imidazolidine, pyridine, piperidine, piperazine, morpholine and phthalimide. The alkylene group formed by bonding Y1 and Y2 to each other preferably has 3-8 carbon atoms. Rings formed by the alkylene group which may be through an oxygen, a nitrogen or a sulfur include pyrrolidine, imidazolidine and piperazine. More preferred as Y1, Y2 and Y3 are a hydrogen atom, and carboxyl, aminomethyl, di-lower alkyl-amino and lower alkyl-aminomethyl groups, with a hydrogen atom, and carboxyl, aminomethyl, dimethylamino and dimethylaminomethyl groups being particularly preferred.
Particularly preferred as W is piperazine or homopiperazine ring which may be substituted by a carboxyl, aminomethyl, di-lower alkyl-amino or di-lower alkyl-aminomethyl group, or 
Incidentally, in the general formula (1), A is not a phenyl group when B is a p-phenylene group, and W is a 1,4-piperazinyl group. A is not a phenyl group which may be substituted when B is xe2x80x94CHxe2x95x90CHxe2x80x94.
The salts of the diamide compounds (1) may be any salts so far as they are pharmaceutically acceptable salts. Examples thereof include mineral acid salts such as sulfates; organic acid salts such as methanesulfonates, acetates, oxalates and citrates, and besides in the case where the diamide compounds (1) are acidic compounds, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and organic basic salts such as pyridine salts, picoline salts and triethylamine salts.
The diamide compounds (1) may be present in the form The diamide compounds (1) can be prepared in accordance with, for example, the following reaction formula: 
More specifically, the compounds (1) according to the present invention are obtained by the N-acylating reaction of a carboxylic acid (2) or a reactive derivative thereof with an amine (3).
The N-acylating reaction may be conducted by using any N-acylating reaction known per se in the art. It is particularly preferable to apply, for example, (a) a method in which the carboxylic acid (2) and the amine (3) are reacted in the presence of a base and/or a condensation agent in a solvent, or (b) a method in which a reactive derivative of the carboxylic acid (2) and the amine (3) are reacted in a solvent.
Examples of the solvents used in these reactions may include dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, methylene chloride and dichloroethane. Examples of the base may include organic bases such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as sodium carbonate and sodium hydrogencarbonate. Examples of usable condensation agents include 1,3-dicyclohexylcarbodiimide, 1-cyclohexyl-3-morpholinoethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1,1xe2x80x2-carbonyldiimidazole, diethyl phosphorocyanidate, diphenylphosphoryl azide, bis(2-oxo-3-oxazolidinyl)phosphinic chloride and 2-chloro-1-methylpyridinium iodide. Examples of usable derivatives of the carboxylic acid include acid halides such as acid chlorides, acid azides, symmetric acid anhydrides, mixed anhydrides with pivalic acid or the like, and active esters such as cyanomethyl esters and p-nitrophenyl esters.
In each of the method (a) and the method (b), the N-acylating reaction is completed by reacting the carboxylic acid (2) or the reactive derivative thereof with the amine (3) at a reaction temperature of 0xc2x0 C. to 100xc2x0 C. for 30 minutes to 30 hours. The isolation and purification of the compound (1) from the reaction mixture may be conducted by using any methods known per se in the art, for example, filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography.
The compound (1) thus obtained may be converted into an acid-addition salt in a method known per se in the art.
The compound may also be converted into a solvate with a solvent for reaction, a solvent for recrystallization, or the like, in particular, a hydrate.
Since the diamide compounds (1) according to the present invention have an excellent inhibitory effect on the production of an IgE antibody, they are useful as medicines for prevention and treatment of various allergic immunological diseases, in which IgE participates, for example, asthma, atopic dermatitis, allergic rhinitis, inflammatory bowel diseases and contact dermatitis.
The diamide compounds (1) or the salts thereof can be formulated into various oral and parenteral preparations in the form of a solid, semisolid or liquid by adding a pharmaceutically acceptable carrier in accordance with a method known per se in the art.
Examples of the oral preparations include tablets, pills, granules, soft and hard capsules, powders, grains, triturations, emulsions, syrups, pellets and elixirs. Examples of the parenteral preparations include injections, drops, infusions, ointments, lotions, tonics, sprays, inhalation suspensions, oils, emulsions and suppositories. The active ingredients according to the present invention may be formulated into various preparations in accordance with a method known per se in the art. In these preparations, may be used surfactants, excipients, colorants, smell corrigents, preservatives, stabilizers, buffers, suspension stabilizers, isotonic agents and the like, as needed.
The dose of the diamide compound (1) or the salt thereof varies according to the kind of the compound, the kind of a disease to be treated or prevented, an administration method, the condition, age, sex, weight of a patient to be administered, treatment time, and the like. However, the compound may be administered in a dose of 0.01-1,000 mg/kg (weight)/day. The compound may be administered at once or in several portions, for example, 2 to 6 portions a day.